Real-time visualisation of organic crystal growth dynamics during liquid reagent mixing by liquid cell transmission electron microscopy

Abstract Liquid cell transmission electron microscopy (LCTEM) is a powerful technique for revealing crystallisation dynamics with nm spatial resolution. However, the study of liquids while mixing precursor solutions is extremely challenging. Here, we show how the antisolvent-driven crystallisation of an organic crystal, a widely-employed precipitation route in the pharmaceutical industry, can be visualised directly in a commercially-available liquid cell by flushing the antisolvent past a thin layer of solvent while recording scanning transmission electron microscopy (STEM) images in real-time. Our results reveal particles forming chain-like structures during antisolvent-mediated growth, whereas they coalesce to form single large particles in the absence of an antisolvent. Our approach of mixing the liquids in sequence and using STEM mode to record images with precise electron dose control establishes a platform for novel LCTEM studies of a wide range of electron-beam-sensitive materials, including drug molecules, polymers and molecular amphiphiles that are created during reagent mixing.